Allostatic Load & Epigenetic Mechanisms in Lifecourse Trajectories of Premature Infants at Age 30 Among the most intense experiences of adversity for infants is premature birth. Annually, 1 in 10 (450,000 in the US, 15 million worldwide) infants are born prematurely. The societal cost of preterm birth in the US is estimated to be $26 billion/year. An infant's early birth marks the beginning of a long trajectory that broadly impacts families, health care, education, social systems, and the survivors themselves. Yet, studies of premature infants at adulthood are few compared to those at younger ages and most focus on the smallest 20% of premature infants. We do know that their transition to adulthood is challenging, and often hampered by cognitive, physical and mental health, motor and independence difficulties. In this application, we respond to an Institute of Medicine recommendation for long-term outcome studies into young adulthood for premature infants. We now propose the 10th wave at 30-33 years of age for a well-characterized preterm sample of 215 infants representing a wide range of neonatal morbidity, birth weight, and all SES strata. We have retained 96% of the sample between ages 17 and 23 years, and 85% since birth. In a prospective, longitudinal design, the specific aims are to: (1) Determine the lifecourse and cumulative impact of medical risk, socioeconomic risk, and protection on adult outcomes of physical and psychological health, adaptive function, executive function, work, and social competence to age 30y; (2) Determine the allostatic load across prematurity groups and socioeconomic levels, and its impact on outcomes of physical and psychological health, adaptive function, executive function, work, and social competence to age 30y; and in exploratory aim (3), examine and compare epigenomewide DNA methylation and estimates of age acceleration (Horvath's epigenetic clock) across full- term and preterm groups at age 30y. Variability of DNA methylation and the `clock' across preterm groups and gender will be examined as well as the association with 30y cardiovascular indicators of obesity. We will explore longitudinal associations between medical risk, SES, and protection with the epigenetic clock. The project represents collaboration between the University of Rhode Island, Memorial Hospital of Rhode Island, and the University of California Irvine. The interdisciplinary research team is comprised of experts in nursing, medicine, developmental pediatrics, stress and psychoneuroendocrinology, nutrition, epigenetics and biostatistics. The analysis approach includes adjusted models (e.g. linear regression model for continuous, logistic regression for binary, generalized odds model for categorical outcomes). Linear mixed models (LMM) and generalized linear mixed models (GLMM) with both fixed and random effects of time included in the models to examine the differences in trajectories of the outcome variables over time. Appropriate covariates will be assessed at baseline and all data points if applicable. Given the state of the science, the proposed project takes a novel lifecourse perspective that accounts for the stress of the neonatal period, the cumulative developmental context (risk, protection), molecular and epigenetic mechanisms, and individual resilience over time. The allostatic load index adds a cumulative measure of biological risk since it captures cumulative physiological effects across major regulatory systems. We will explore epigenomewide DNA methylation as a mechanism underlying allostatic load processes. Both allostatic load and DNA methylation build on a stress paradigm theorized at Developmental Origins Theory of Health and Disease. In this project we propose a synthesis in a lifecourse perspective to determine how prematurity and environmental stress effect preterm-to- adult health. To our knowledge, this would be the only U.S. study of premature infants to age 30-33y. Thus, there is limited research-based evidence to inform the timing and content for interventions despite millions of preterm survivors.